The main objective of this research program is to advance our understanding of an important subset of leukocytes called myeloid-derived suppressor cells (MDSCs) so that new MDSC-based strategies can be developed to treat cancer. Although MDSCs are present in low numbers in healthy individuals, they increase markedly in patients with cancer or chronic inflammation (comprising up to 10% of leukocytes in the blood or spleen). This increase is resulted from aberrant myelopoiesis driven by inflammatory mediators. MDSCs, but not monocytes or neutrophils, are potent suppressors of immune responses. Depletion of MDSCs leads to markedly enhanced anti-tumor immunity, and may be crucial for the success of cancer immunotherapy. Phenotypically, MDSCs are similar to monocytes and neutrophils, but functionally and biochemically they are distinct from the latter cell subsets. MDSCs are ?polarized? immature myeloid cells, producing selectively inhibitory but not inflammatory mediators of myeloid cells. Despite their significance in cancer and inflammatory diseases, MDSCs remain to be one of the least understood subsets of leukocytes. It is unclear what specifies the polarized differentiation program of MDSCs; it is unknown how the inflammatory property of the myeloid lineage is held in check in MDSCs. This grant application is inspired by our recent discovery that MDSCs may utilize a unique polarization signaling complex to control its development and function. The complex consists of a phosphoinositide lipid second messenger and its professional transfer protein TIPE2 (tumor necrosis factor-a-induced protein 8-like 2 or TNFAIP8L2). TIPE2 contains a large hydrophobic cavity constitutively occupied by the phosphoinositide second messenger. Importantly, TIPE2-deficient tumor-bearing mice have a significant defect in the generation and/or function of Gr1+CD11b+ MDSCs. As a consequence, tumor growth in these mice is significantly diminished. In this proposal, we will test the hypotheses that (i) the TIPE2 polarization complex directs both the development and function of myeloid-derived suppressor cells, and (ii) the dual functionality of TIPE2 specifies the polarization signaling program of myeloid-derived suppressor cells.